Nasallly applicable pharmaceutical preparation and the production thereof

ABSTRACT

The invention relates to a novel pharmaceutical preparation which can be administered nasally and is based on an aqueous solution, emulsion or the like which comprises at least one mucosally absorbable and/or locally acting active pharmaceutical ingredient, at least one preservative formed by benzalkonium chloride alone or together with other preservative substances, at least one buffer which keeps the pH at 4 to 6, and in addition at least one osmotic agent and/or at least one wetting agent and which is characterized in that the preparation has a substantially improved ciliary tolerability owing to the fact that in the preparation a buffer based on malic acid is present instead of a buffer which has been employed to date in the pharmaceutical preparation and is based on citrate(s), phosphate(s) and/or acetate(s)—partly or completely replacing it (them)—while retaining the composition, concentration and amount ratios, intended in each case for the pharmaceutical preparation, of active ingredient(s), preservative(s), osmotic agent(s) and wetting agent(s). It further relates to a process for producing the preparation and to the use of a malic acid buffer in the preparation.

The present invention relates to liquid preserved pharmaceuticalpreparations for administering various active ingredients on or in orvia the nose of a patient in the form of a solution, to the productionthereof and to the use of a specific buffer system for and in saidpreparations.

A large number of medicaments which can be administered in particular inthe form of solutions and/or emulsions into the nose of a patientexists, either in the form of nasal drops or, increasingly recently,especially in the form of nasal sprays. These pharmaceuticalpreparations which can be administered nasally can be used either forthe treatment or for the prevention of disorders of the nose itself, orelse are intended to lead to uptake of active ingredients into thebloodstream, so that they display an effect elsewhere in the body.

Representatives which should be mentioned of the first-mentioned groupof medicaments which can be administered nasally are, in particular,agents or active ingredients against nasal catarrh, such as allergyremedies such as, for example, cromoglicic acid, or sympathomimeticssuch as, for example, xylometazoline, tetrazoline, oxymetazoline,naphazoline, phenylephrine.

One example of the second group of such medicaments is represented forinstance by peptide preparations such as, for example, those havingdesmopressin as active ingredient, which is an effective agent for thetreatment of diabetes insipidus. Most such nasal sprays or nasal dropswhich are intended as medicaments comprise, besides at least one activeingredient,

substances to adjust a particular osmotic pressure (e.g. NaCl) and/orwetting or surface-active substances (e.g. Cremophors), also

excipients to stabilize the active ingredient or to maintain aparticular physiologically acceptable pH in the nose. To date, phosphateor phosphate/citrate or citrate buffers and, in some circumstances, alsoacetate buffers have been employed almost exclusively for this purpose.In addition, in most cases they contain

benzalkonium chloride as preservative.

Benzalkonium chloride, abbreviated to BAC, has been employed widely aseffective antiseptic and preservative since its introduction in 1935.There are reports in the scientific literature that it is well toleratedon the skin and on mucous membranes because it has scarcely any irritanteffect (H. P. T. Ammon, Arzneimittelneben-and-wechselwirkungen, chapter69: 1211; 1991, Mutschler E., Arzneimittelwirkungen, Lehrbuch derPharmakologie und Toxikologie, chapter 9: 642; 1997).

Benzalkonium chloride is therefore employed very widely in disinfectantsfor the mouth and throat and for wound irrigation and vaginal douching.Because of the good antimicrobial activity and the good tolerability, itis the most frequently employed preservative, which is employed in nasalsprays and eye drops in conjunction with a large number of activepharmaceutical ingredients.

Ciliated epithelium, which is the ciliary apparatus of the nasal mucosawhich is extremely important for maintaining the physiological functionof the nose, is considerably impaired, in some cases even irreversibly,by the preservative benzalkonium chloride (Klöcker and Rudolph, P Z 145(21) 40-42, 2000; Hofmann, et al. HNO 1998; 46 (2): 146-151; Neugebaueret al., annual meeting of the German society for otorhinolaryngology,head and neck surgery, 1998.

Some authorities in the European Union have in fact for this reasonproposed or required a massive restriction of the use of thispreservative (German Federal Institute for drugs, graduated planprocedure II, Bundesanzeiger No. 120, Jul. 3, 2002), although nasalsprays with benzalkonium chloride as preservative are currently used totreat, besides nasal catarrhal and allergic disorders directly affectingthe respiratory system, also numerous chronic disorders which are oftenin fact life-long.

Pharmaceutical preparations, which are entirely free of preservativesare demanded as the only remedy for these problems deriving from theadverse effect of BAC on the ciliary apparatus. However, thesepreparations are associated with considerable economic expenditure. Itis necessary to employ special nasal spray systems, and, inter alia, allpackaging materials and sprayer parts which come into contact with thenasal spray solution must be subjected to elaborate sterilization withhighly toxic chemicals and/or radioactive beams, which is, after all,not precisely desired either.

During detailed investigations with the purpose of finding a feasibleremedy for this, it has emerged in a perfectly surprising manner that itis possible by use of a very particular, specific buffer system—knownper se as such—to eliminate at least a large part of the damaging effecton the cilia and their activity of BAC which is valued and approved aspreservative in its other properties.

The present invention thus relates to a novel pharmaceutical preparationwhich can be administered nasally and is based on an aqueous solution,emulsion or the like which comprises at least one mucosally absorbableand/or locally acting active pharmaceutical ingredient known per se, atleast one preservative formed by benzalkonium chloride alone or togetherwith other preservative substances, at least one buffer which keeps thepH at 4 to 6 or at about 5, and in addition at least one osmotic agentand/or at least one wetting agent and which is characterized in that thepreparation has a substantially improved ciliary tolerability owing tothe fact that in the same solution, emulsion or the like, or in the oneunderlying it, a buffer based on malic acid is present instead of abuffer which has been employed to date in the pharmaceutical preparationand is based on citrate(s), phosphate(s) and/or acetate(s)—partly orcompletely replacing it (them)—while retaining the composition,concentration and amount ratios, intended in each case for thepharmaceutical preparation, of active ingredient(s), preservative(s),osmotic agent(s) and wetting agent(s).

The present invention is a case which is not so common in the field ofpharmaceutical preparations, where the essence thereof consists not of anovel active ingredient and the use thereof in a medicament, but on thecontrary in the apparently substantially less spectacular area of anadditive which has long ago become routine and has long been approved inpractice, such as precisely the buffer system which is present in amedicament preparation and is crucial for its activity and stability,and in an unexpectedly beneficial change away from approved andgenerally widely employed buffer systems for liquid pharmaceuticalpreparations towards another buffer which is used substantially lessoften in medicaments.

It is quite essential to emphasize that the advantage of the presentinvention is that the change from the previous buffer system to themalic acid buffer which is now to be employed can take place without analteration in the amount, concentration, composition ratios of the othercomponents including the active ingredients in the various medicamentpreparations approved in practice, while costly rearrangements andauthority procedures can be avoided.

Concerning a previously disclosed use of malic acid buffers incompositions for pharmaceutical and possibly also diagnostic purposes,reference should be made for example to WO 98/47490 which relates tolyophilizates of biomolecules and in which mention is made, besides alarge number of different buffers based on organic acids, also of malicacid, and although the buffers mentioned therein are used to adjust thepH, their main task is to prevent the formation of interfering argininephosphate—or arginine citrate-protein aggregates produced when phosphateor citrate buffers known per se are used.

Mention should further be made, concerning the use of a malic acidbuffer in a pharmaceutical preparation which can be used orallysublingually or nasally and comprises the active ingredientdesmopressin, of our own AT 409 081 B1, according to which a substantialimprovement in the stability of the pharmaceutical preparation can beachieved through the use of the malic acid buffer, whether together withsubstantially reduced amounts of benzalkonium chloride as preservativeor with exclusion thereof.

Neither of the two publications mentioned touches even in the smallestdegree on the problems solved by the present invention, of the damagemainly caused by the approved preservative benzalkonium chloride on theciliary apparatus of the nasal mucosa, which is highly relevantespecially when a medicament preparation which can be administerednasally must be administered over a long period.

The simplest and perfectly effective embodiment for the purpose ofreducing the harmful effect on the cilia of this preservative and, inparticular, also rapid and substantial regeneration of the ciliaryactivity after administration of the medicaments with a wide variety ofmedicament active ingredients comprising the same, as already emphasizedabove, is racemic malic acid as pH stabilizer and agent which preciselyprevents very substantially the harmful effects on the cilia. However,enantiopure malic acid can also be employed instead of racemic malicacid.

Particularly appropriate concentration ranges of the malic acid bufferin the novel pharmaceutical preparation are indicated in Claim 2.

Malic acid buffers in which sodium hydroxide solution is employed toform the counter ion in the buffer system have proved appropriate, as isevident from claim 3.

Claim 4 names NaCl as a particularly appropriate osmotically activeingredient in connection with the cilia-friendly effect of the novelmedicament preparations.

Claim 5 mentions, without claiming completeness, some active ingredientgroups and specific important active ingredients which can be employedin the preparations of the invention with the malic acid buffer.

A further essential aspect of the present invention is formed by theprocess for producing the novel pharmaceutical preparation which can beadministered nasally, details of which are mentioned in claim 6, theessential feature of this production process being the specificreplacement of the buffer systems which have previously beenemployed—and have proved in the course of the investigations for thepresent invention to be—in the presence of benzalkoniumchloride—thoroughly dangerous for ciliary activity, by a malic acidbuffer.

The features of claims 7 and 8, which follow the production claim 6 andrefer back to it, are analogous to the features of claims 2 to 6 alreadyexplained above.

A further essential aspect of the invention consists of the—as describedabove—surprisingly found use, which has not to date been mentioned oreven suggested anywhere, of the buffer system based on malic acid asessential ingredient, instead of buffers customary to date for producingcilia-tolerated pharmaceutical preparations which can be administerednasally, the details not being quoted here and being disclosed in claim9.

The features of claims 10 and 11, which follow the use claim 9 and referto it and likewise refer to the use of a malic acid buffer in themedicament preparations under consideration, are analogous to those ofclaims 2 to 4 and 7 and 8 explained in detail above.

Finally, reference should also be made to the further aspect of theinvention relating to the use of the malic acid buffer system in thenovel pharmaceutical preparations, which is to be found in its entiretyin claim 12.

The invention is explained in more detail by means of the followingexamples.

GENERAL EXAMPLE

In a standard test for examining ciliary function, a conventionalpreparation for nasal administration having a phosphate/citrate bufferand benzalkonium chloride as preservative was compared in each case witha preparation of the invention having malic acid as buffer andbenzalkonium chloride as preservative.

Pieces of tissue from ciliated epithelium of the trachea of chickenembryos are employed in the tests on which the comparison is based,reference being made for details of the tests to S. G. Romejn et al.,Int. J. of Pharmac. 135 (1996) 137-145 and van De Donk et al.,Rhinology, 20 (1982) 81-87.

Active ingredient solution 1

0.335 mg/ml malic acid; 0.168 mg/ml NaOH; 9.115 mg/ml sodium chloride;0.1 mg/ml benzalkonium chloride; pH: 5.07.

Active ingredient solution 2

1.7 mg/ml citric acid; 3 mg disodium phosphate dihydrate; 7.5 mg/mlsodium chloride; 0.1 mg/ml benzalkonium chloride; pH: 5.04. PreparationCiliary frequency Reversibility of with after incubation the effect indesmopressin for 15 min, % of Ringer's solution as active the original(45 min), % of the ingredient frequency; original frequency; (n = 6)standard deviation standard deviation in brackets in brackets Solution 1with  33 (13)  74 (15) malic acid buffer Solution 2 with  6 (7)  48 (18)normal buffer Control with 101 (6) 102 (3) Ringer's solution

After exposure for 15 min, the ciliary frequency is reduced distinctlyless by solution 1 with malic acid buffer than by solution 2 with theusual buffer. The self-cleaning of the nasal mucosa is then simulated bywashing out the respective solutions and adding Ringer's solution for 45min. After this, a distinctly increased, from 48 to 74%, recovery of theciliary frequency is achieved with solution 1 with the malic acidbuffer.

Example 1

4900 g of distilled water are introduced into a 5 l glass beaker and45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 1.675 g ofmalic acid and 5 g of xylometazoline hydrochloride are dissolved thereinby stirring. The pH is adjusted to 5.5 with 1N NaOH. The volume is madeup to 5 l with distilled water, and the resulting solution is furtherprocessed to nasal drops or to a nasal spray.

Example 2

4900 g of distilled water are introduced into a 5 l glass beaker and45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 1.675 g ofmalic acid and 2.5 g of xylometazoline hydrochloride are dissolvedtherein by stirring. The pH is adjusted to 5.5 with 1N NaOH. The volumeis made up to 5 l with distilled water, and the resulting solution isfurther processed to nasal drops or to a nasal spray.

Example 3

4900 g of distilled water are introduced into a 5 l glass beaker and45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 1.675 g ofmalic acid and 12.5 g of phenylephrine hydrochloride are dissolvedtherein by stirring. The pH is adjusted to 5 with 1N NaOH. The volume ismade up to 5 l with distilled water, and the resulting solution isfurther processed to nasal drops or to a nasal spray.

Example 4

4900 g of distilled water are introduced into a 5 l glass beaker and45.58 g of sodium chloride, 0.5 g of benzalkonium chloride, 0.67 g ofmalic acid and 6.25 g of phenylephrine hydrochloride are dissolvedtherein by stirring. The pH is adjusted to 5 with 1N NaOH. The volume ismade up to 5 l with distilled water, and the resulting solution isfurther processed to nasal drops or to a nasal spray.

Summary of the results achieved with the preparations according toexamples 1 to 4 in relation to the substantial improvement in ciliarytolerability.

The composition of the reference solutions for examples 1 to 4 is shownin table 1 below: TABLE 1 Reference Reference Reference Reference 1 2 34 Xylometazoline 1 mg 0.5 mg hydrochloride Phenylephrine 2.5 mg 1.25 mgbase Sodium 5 mg 5 mg dihydrogenph. dihydrate Sodium mono-hydrogenphosphate 1.7 mg 1.7 mg dodecahydrate Disodium 4.6 mg 2.3 mghydrogenphosphate Citric acid. H₂O 2.6 mg 1.3 mg Disodium edetate 0.45mg 0.45 mg Benzalkonium 0.1 mg 0.1 mg 0.1 mg 0.1 mg chloride Sorbitol 21mg 21 mg 50 mg 60 mg Sodium chloride 5 mg 5 mg Water ad 1 ml ad 1 ml ad1 ml ad 1 ml

The comparative results relating to ciliary tolerability are summarizedin table 2. TABLE 2 Ciliary frequency Reversibility of the afterincubation for effect in Ringer's 15 min, % of the solution (45 min), %original frequency; of the original standard deviation in frequency;standard Preparation brackets deviation in brackets Solution of 29 (16)71 (16) example 1 Reference 12 (5) 36 (15) solution 1 Solution of 34(12) 79 (19) example 2 Reference 18 (6) 41 (11) solution 2 Solution of36 (11) 68 (18) example 3 Reference 17 (7) 29 (13) solution 3 Solutionof 38 (14) 77 (16) example 4 Reference 15 (8) 40 (14) solution 4

After exposure for 15 min, the ciliary frequency is reduced distinctlyless by the exemplary solutions with malic acid buffer than by thereference solutions. The self-cleaning of the nasal mucosa is thensimulated by washing out the test solutions and adding Ringer's solutionfor 45 min. A distinctly better recovery of the ciliary beating force,which extends to more than ¾ of the initial beating force (of 100%), isachieved thereby with the exemplary solutions with malic acid buffer.This value is very good, especially since only 55% of the initialciliary frequency are obtained after 45 mins even on incubation of thecilia in physiological saline solution.

Example 5

A nasal spray with benzalkonium chloride as preservative for treatingdiuretic impairments and bleeding disorders is produced by introducing990 g of water for injections into a 1 l glass beaker and dissolvingtherein 9.115 g of sodium chloride, 0.1 g of desmopressin acetate, 0.1 gof benzalkonium chloride and 0.335 g of malic acid. The pH is adjustedto 5 with 4.2 ml of 1N NaOH, and then the volume is made up to 1 l, andthe solution is filtered through a Millipak filter and dispensed inamber glass bottles which are closed with pump attachments. Theproduction and dispensing of the solution take place in pharmaceuticalmanufacturing rooms under low-microbe conditions.

The results obtained in orienting tests with the active ingredientsolution of example 5 were quite analogous to the results listed intable 2 above in terms of substantially less reduction in ciliaryactivity and improved regeneration of the cilia.

The results obtained in further, likewise orienting tests with theactive ingredients calcitonin (from salmon) for the treatment ofosteoporosis and cromoglicic acid for the treatment of allergic nasalcatarrh were similar.

1-16. (canceled)
 17. A buffered pharmaceutical preparation for nasaladministration, the preparation comprising: water; at least one nasallyadministrable active pharmaceutical ingredient; at least onepreservative comprising benzalkonium chloride; at least one bufferkeeping the pH at 4 to 6, said at least one buffer comprising a malicacid compound; and at least one agent selected from the group consistingof an osmotic agent and a wetting agent; said preparation havingsubstantially improved ciliary tolerability.
 18. The preparationaccording to claim 17, wherein said malic acid compound is present in aconcentration in a range from 1 to 5 millimoles per liter of saidpharmaceutical preparation.
 19. The preparation according to claim 17,wherein said buffer is formed with sodium as counter ion.
 20. Thepreparation according to claim 17, wherein said malic acid compound isselected from the group consisting of racemic malic acid and enantiopuremalic acid.
 21. The preparation according to claim 17, wherein saidosmotic agent comprises sodium chloride.
 22. The preparation accordingto claim 17, wherein said active pharmaceutical ingredient is selectedfrom the group consisting of at least one allergy remedy, at least onesympathomimetic remedy, at least one nasal catarrh remedy, at least onecorticoid, at least one peptide, and at least one hormone.
 23. Thepreparation according to claim 17, wherein said active pharmaceuticalingredient is selected from the group consisting of levocabastine,azelastine, cromoglicic acid, xylometazoline, tetrazoline, indanazoline,phenylephrine, naphazoline, tramazoline, oxymetazoline, beclometasone,triamcinolone, calcitonin, desmopressin, gonadorelin, buserelin,nafarelin, and oxytocin.
 24. The preparation according to claim 17,wherein said active pharmaceutical ingredient is calcitonin.
 25. Thepreparation according to claim 17, wherein said active pharmaceuticalingredient is cromoglycic acid.
 26. The preparation according to claim17, wherein said active pharmaceutical ingredient is desmopressin. 27.The preparation according to claim 17, wherein said activepharmaceutical ingredient is phenylephrine.
 28. The preparationaccording to claim 17, wherein said active pharmaceutical ingredient isxylometazoline.
 29. The preparation according to claim 17, additionallycomprising a buffer selected from the group consisting of a citratebuffer, a phosphate buffer, and an acetate buffer.
 30. The preparationaccording to claim 17, being an emulsion.
 31. The preparation accordingto claim 17, being a solution.
 32. The preparation according to claim17, wherein said active pharmaceutical ingredient is mucosallyabsorbable.
 33. The preparation according to claim 17, wherein saidactive pharmaceutical ingredient is locally effective.
 34. A method oftreating a condition selected from the group consisting of allergy,bleeding disorder, diuretic impairment, and osteoporosis, comprising theintranasal administration to a person in need of such treatment of thepreparation according to claim
 17. 35. The method of claim 34, whichcomprises treating the person by administering the preparation via anasal spray.
 36. The method of claim 34, which comprises treating theperson by administering the preparation via nose drops.
 37. A method ofpreparing a buffered pharmaceutical preparation for nasal administrationand having substantially improved ciliary tolerability, the method whichcomprises: providing water; admixing at least one nasally administrableactive pharmaceutical ingredient; admixing at least one preservativecomprising benzalkonium chloride and at least one agent selected fromthe group consisting of an osmotic agent and a wetting agent; andbuffering the preparation to a pH of 4 to 6 with at least one buffer atleast primarily comprising a malic acid compound.